DOCSLIB.ORG

Roles of Retinoic Acid and Cyp26 Inhibitors in Ovarian Follicle Development

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Roles of Retinoic Acid and Cyp26 Inhibitors in Ovarian Follicle Development View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Via Sapientiae: The Institutional Repository at DePaul University DePaul University Via Sapientiae College of Science and Health Theses and Dissertations College of Science and Health Summer 8-22-2014 Roles of Retinoic Acid and Cyp26 Inhibitors in Ovarian Follicle Development Shruti M. Kamath DePaul University, [email protected] Follow this and additional works at: https://via.library.depaul.edu/csh_etd Recommended Citation Kamath, Shruti M., "Roles of Retinoic Acid and Cyp26 Inhibitors in Ovarian Follicle Development" (2014). College of Science and Health Theses and Dissertations. 79. https://via.library.depaul.edu/csh_etd/79 This Thesis is brought to you for free and open access by the College of Science and Health at Via Sapientiae. It has been accepted for inclusion in College of Science and Health Theses and Dissertations by an authorized administrator of Via Sapientiae. For more information, please contact [email protected]. Roles of Retinoic Acid and Cyp26 Inhibitors in Ovarian Follicle Development A Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Master of Science August, 2014 BY Shruti M Kamath Department of Biological Sciences College of Science and Health DePaul University Chicago, Illinois 1 Table of Contents Title Page………………………………………………………………………………………..1 Table of Contents……………………………………………………………………………...2 Acknowledgements……………………………………………………………………………4 Introduction ................................................................................................................... 5 Review Of Background Literature................................................................................ 5 Ovarian follicle development in mammals ................................................................... 5 Ovarian diseases......................................................................................................... 8 Retinoic Acid ............................................................................................................... 9 Role of Retinoic Acid in gonads ................................................................................ 12 Imbalances, Dysfunctions and the Importance of RA signaling ................................. 14 Cyp26 Enzymes ........................................................................................................ 16 Retinoic Acid Metabolism Blocking Agents ............................................................... 18 Liarozole .......................................................................................................... 18 R115866 ........................................................................................................... 19 Mice as a model for ovarian follicle development studies .......................................... 20 Follicle culture as an in vitro model ........................................................................... 20 Experimental Designs and Methodology .................................................................. 24 Animals ..................................................................................................................... 24 Follicle cell culture, collection and treatment ............................................................. 24 Monitoring follicle and oocyte growth and follicle morphology ................................... 26 Ovary culture, collection and treatment ..................................................................... 26 Follicle counting for ovary culture .............................................................................. 28 Immunohistochemistry .............................................................................................. 29 Statistics .................................................................................................................... 31 Hypothesis ................................................................................................................... 32 Results ......................................................................................................................... 33 3 Effects of RA,R115866 and Liarozole on the growth of in vitro cultured follicles ....... 33 Effects of RA on the growth of in vitro cultured follicles ............................................. 36 Effects of R115866 on the growth of in vitro cultured follicles ................................... 38 Effects of Liarozole on the growth of in vitro cultured follicles ................................... 41 Effects of RA, R115866 and Liarozole on in vitro cultured ovaries ............................ 44 Follicle count ............................................................................................................. 44 Immunohistochemistry .............................................................................................. 48 Cyp26b1 expression ................................................................................................. 48 Presence of apoptosis ............................................................................................... 50 Discussion ................................................................................................................... 52 RA has a moderate effect on follicle development .................................................... 52 R115866 showed a significant effect on follicle development: .................................. 53 Liarozole showed a strong stimulatory effect on follicle growth and development .... 53 Stimulatory effects of RA and Cyp26b1 Inhibitors on whole ovary development ....... 54 Cyp26b1 expression was seen throughout the ovary ................................................ 54 Apoptosis was measured amongst treatment groups................................................ 55 High doses of RA are toxic to follicles and granulosa cells ....................................... 55 References ................................................................................................................... 57 3 Acknowledgments I thank Dr. Jingjing Kipp for welcoming me into her lab and for her mentorship over the past 2 years. During this time, I had the opportunity learn several cutting edge and skillful laboratory techniques and got a chance to hone my presentation skills. This experience has been invaluable. I would also like to thank my committee members, Drs. Talitha Rajah and Eric Norstrom. Both my committee members were extremely supportive and always willing to help me put together my work to present it in the form of a thesis. The work from which this thesis was derived was performed by Kipp lab members, Michael Demczuk and Tessa Bonny, whom I thankful to for setting the groundwork for my project. I also worked closely with Michael Akroush as co-presenters at both a poster session and data club. His help in the lab, especially with validating the IHC protocol and perfecting the protocol, was definitely helpful and is greatly appreciated. I also thank DePaul University and the College of Science and Health for awarding me with the Graduate Research Fund Grant. In addition to DePaul University, I would like to thank the Northwestern Histology Core for providing us with their histology services and lastly, but definitely not the least, Dr. Kelly Mayo for his continued support and Teresa Woodruff and Dr. Min Xu, for sharing and providing us with the training required to perform the follicle culture per their 2D follicle culture protocol. 3 Introduction The ovaries are the female reproductive organs that are located on either side of the uterus. They contain eggs and secrete hormones that are critical for female reproduction. Each follicle consists of an egg at the center, surrounded by multiple layers of somatic cells. These eggs undergo various stages of development wherein the follicular structure matures as a whole; the hormones and growth factors secreted by the somatic cells are essential for the maturation of the egg while the signaling molecules produced by the egg are crucial for somatic cell proliferation and follicle maturation and development. Thus, mammalian ovarian follicle formation and development involves the establishment of the initial follicle pool, follicle growth, proper maturation of eggs, and timely production and release of hormones and the mature eggs. This process is essential for propagation of the species as well as for development and homeostasis of the female reproductive system[1]. Abnormalities in the regulation and development of ovarian follicles such as inadequate maturation of the follicle due to inadequate cell-cell interactions and signaling between the somatic cells and the egg can lead to infertility and ovarian diseases, for instance Premature Ovarian Failure (POF), Polycystic Ovary Syndrome (PCOS) and ovarian cancer. These diseases lead to a loss of fertility due to the formation of immature or unhealthy follicles and/or oocyte development. Both intraovarian and extraovarian factors play a role in regulating the development of follicles. However, factors involved in follicular growth and survival are not well defined. Recently, studies have suggested that the 3 potent morphogen retinoic acid (RA) plays a role in the development of a healthy ovary[1, 2]. However, the underlying mechanism is not understood. Germ cells in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective
Load more

Recommended publications
  • Identification and Developmental Expression of the Full Complement Of
    Goldstone et al. BMC Genomics 2010, 11:643 http://www.biomedcentral.com/1471-2164/11/643 RESEARCH ARTICLE Open Access Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish Jared V Goldstone1, Andrew G McArthur2, Akira Kubota1, Juliano Zanette1,3, Thiago Parente1,4, Maria E Jönsson1,5, David R Nelson6, John J Stegeman1* Abstract Background: Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Results: Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates.
    [Show full text]
  • Synonymous Single Nucleotide Polymorphisms in Human Cytochrome
    DMD Fast Forward. Published on February 9, 2009 as doi:10.1124/dmd.108.026047 DMD #26047 TITLE PAGE: A BIOINFORMATICS APPROACH FOR THE PHENOTYPE PREDICTION OF NON- SYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS IN HUMAN CYTOCHROME P450S LIN-LIN WANG, YONG LI, SHU-FENG ZHOU Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, P. R. China (LL Wang & Y Li) Discipline of Chinese Medicine, School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia (LL Wang & SF Zhou). 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. DMD #26047 RUNNING TITLE PAGE: a) Running title: Prediction of phenotype of human CYPs. b) Author for correspondence: A/Prof. Shu-Feng Zhou, MD, PhD Discipline of Chinese Medicine, School of Health Sciences, RMIT University, WHO Collaborating Center for Traditional Medicine, Bundoora, Victoria 3083, Australia. Tel: + 61 3 9925 7794; fax: +61 3 9925 7178. Email: [email protected] c) Number of text pages: 21 Number of tables: 10 Number of figures: 2 Number of references: 40 Number of words in Abstract: 249 Number of words in Introduction: 749 Number of words in Discussion: 1459 d) Non-standard abbreviations: CYP, cytochrome P450; nsSNP, non-synonymous single nucleotide polymorphism. 2 DMD #26047 ABSTRACT Non-synonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment and conducting individualized pharmacotherapy.
    [Show full text]
  • Impaired Hepatic Drug and Steroid Metabolism in Congenital Adrenal
    European Journal of Endocrinology (2010) 163 919–924 ISSN 0804-4643 CLINICAL STUDY Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Dorota Tomalik-Scharte1, Dominique Maiter2, Julia Kirchheiner3, Hannah E Ivison, Uwe Fuhr1 and Wiebke Arlt School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK, 1Department of Pharmacology, University Hospital, University of Cologne, 50931 Cologne, Germany, 2Department of Endocrinology, University Hospital Saint Luc, 1200 Brussels, Belgium and 3Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, 89019 Ulm, Germany (Correspondence should be addressed to W Arlt; Email: [email protected]) Abstract Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug- metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes.
    [Show full text]
  • Inhibition of the All Trans-Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous Atra Signaling
    DMD Fast Forward. Published on April 26, 2017 as DOI: 10.1124/dmd.117.075341 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 75341 Inhibition of the all trans-retinoic acid hydroxylases CYP26A1 and CYP26B1 results in dynamic, tissue-specific changes in endogenous atRA signaling Faith Stevison, Cathryn Hogarth, Sasmita Tripathy, Travis Kent, and Nina Isoherranen Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (F.S., S.T., N.I.) School of Molecular Biosciences and the Center for Reproductive Biology, Washington State Downloaded from University, Pullman, Washington (C.H., T.K.) dmd.aspetjournals.org at ASPET Journals on September 28, 2021 1 DMD Fast Forward. Published on April 26, 2017 as DOI: 10.1124/dmd.117.075341 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 75341 Dynamic changes in atRA signaling after CYP26 inhibition Corresponding Author: Dr. Nina Isoherranen, Department of Pharmaceutics, School of Pharmacy, University of Washington, Health Sciences Building Room H-272M, Box 357610, Seattle, WA 98195-7610 USA, Phone: 206-543-2517, Fax: 206-543-3204, E-mail: [email protected] Text Pages: 20 Tables: 0 Downloaded from Figures: 7 References: 40 dmd.aspetjournals.org Words in the abstract: 248 Words in the introduction: 715 Word in discussion: 1500 at ASPET Journals on September 28, 2021 Abbreviations: ALDH1A, aldehyde dehydrogenase 1A family; atRA, all-trans retinoic acid;
    [Show full text]
  • Cyp26b1 Restrains Murine Heart Valve Growth During Development Neha
    bioRxiv preprint doi: https://doi.org/10.1101/2021.07.05.450958; this version posted July 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Cyp26b1 restrains murine heart valve growth during development Neha Ahuja1†, Max S. Hiltabidle1†, Hariprem Rajasekhar2, Haley R. Barlow1, Edward Daniel3, Sophie Voss1, Ondine Cleaver1* and Caitlin Maynard4* 1Departments of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, USA 75390, 2Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ, USA 08901, 3John T. Milliken Department of Medicine, Washington University School of Medicine, 4960 Children’s Place, Suite 6602, St. Louis, MO 63110, and 4Department of Biological Sciences, University of Texas at Dallas, 800 W. Campbell Road, Richardson, Texas, USA, 75080 † These authors contributed equally. * Co-corresponding authors: Ondine Cleaver, PhD Department of Molecular Biology, University of Texas Southwestern Medical Center 5323 Harry Hines Blvd., NA8.300 Dallas, Texas 75390-9148, USA. Phone: (214) 648-1647 Fax: (214) 648-1196 E-mail: [email protected] Caitlin Maynard, PhD Department of Biological Sciences The University of Texas at Dallas 800 W. Campbell Road, FO31 Richardson, TX 75080-3021, USA Phone: (972) 883-6895 Email: [email protected] Running title: Cyp26b1 essential for murine heart valve development Keywords: Cyp26b1, endothelial cell proliferation, aortic valve, pulmonary valve, tricuspid valve, mitral valve 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.05.450958; this version posted July 5, 2021.
    [Show full text]
  • Robert Foti to Cite This Version
    Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses Robert Foti To cite this version: Robert Foti. Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses. Agricultural sciences. Université Nice Sophia Antipolis, 2016. English. NNT : 2016NICE4033. tel-01376678 HAL Id: tel-01376678 https://tel.archives-ouvertes.fr/tel-01376678 Submitted on 5 Oct 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Université de Nice-Sophia Antipolis Thèse pour obtenir le grade de DOCTEUR DE L’UNIVERSITE NICE SOPHIA ANTIPOLIS Spécialité : Interactions Moléculaires et Cellulaires Ecole Doctorale : Sciences de la Vie et de la Santé (SVS) Caractérisation des substrats xénobiotiques et des inhibiteurs des cytochromes CYP26A1, CYP26B1 et CYP26C1 par modélisation moléculaire et études in vitro présentée et soutenue publiquement par Robert S. Foti Le 4 Juillet 2016 Membres du jury Dr. Danièle Werck-Reichhart Rapporteur Dr. Philippe Roche Rapporteur Pr. Serge Antonczak Examinateur Dr. Philippe Breton Examinateur Pr. Philippe Diaz Examinateur Dr. Dominique Douguet Directrice de thèse 1 1. Table of Contents 1. Table of Contents ..............................................................................................................................
    [Show full text]
  • Effects of Retinoids on the TGF-ß System and Extracellular Matrix In
    J Am Soc Nephrol 12: 2300–2309, 2001 Effects of Retinoids on the TGF-␤ System and Extracellular Matrix in Experimental Glomerulonephritis CHRISTIAN MORATH,* CLAUDIUS DECHOW,* INGO LEHRKE,* VOLKER HAXSEN,* RUDIGER¨ WALDHERR,* JURGEN¨ FLOEGE,† EBERHARD RITZ,* and JURGEN¨ WAGNER* *Department of Nephrology, University of Heidelberg, Heidelberg, Germany; and †Department of Nephrology, University of Aachen, Aachen, Germany. Abstract. Transforming growth factor–␤1 (TGF-␤1) overex- compared with untreated animals (P Ͻ 0.025). Cortical expres- pression plays a key role in the glomerular accumulation of sion of TGF receptor II, but not receptor I gene expression, was extracellular matrix proteins in renal disease. Retinoids have significantly lower in animals treated with all-trans retinoic previously been shown to significantly limit glomerular dam- acid or isotretinoin (P Ͻ 0.05). In all-trans retinoic acid–treated age in rat experimental glomerulonephritis. Therefore, the ef- animals with Thy-GN, the increase of glomerular TGF-␤1 fects of all-trans retinoic acid and isotretinoin on the compo- protein (P Ͻ 0.008) and TGF-␤1(P Ͻ 0.025) and TGF nents of the TGF-␤ system and extracellular matrix proteins in receptor II mRNA (P Ͻ 0.015) was significantly less. Immu- anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle- nohistochemistry revealed less glomerular staining for TGF-␤1 injected control rats were compared with rats treated with daily and TGF receptor II in the presence of all-trans retinoic acid. subcutaneous injections of 10 mg/kg body wt all-trans retinoic TGF-␤1 immunostaining was not restricted to monocytes and acid or 40 mg/kg body wt isotretinoin (n ϭ 9 per group) either macrophages, as indicated by double-staining.
    [Show full text]
  • Immunofluorescence Localization of Nuclear Retinoid Receptors In
    Acta Derm Venereol 2004; 84: 363–369 INVESTIGATIVE REPORT Immunofluorescence Localization of Nuclear Retinoid Receptors in Psoriasis Versus Normal Human Skin Teresa KARLSSON, Ola ROLLMAN, Anders VAHLQUIST and Hans TO¨ RMA¨ Department of Medical Sciences, Section of Dermatology and Venereology, Uppsala University, Sweden Psoriasis responds favourably to treatment with retinoids retinoids (1). A second class of retinoid receptors, but the cellular pathways mediating these effects are RXRa,-b and -c, are activated by 9-cis-RA and poorly understood. Retinoids regulate keratinocyte pro- phytanic acid, and function as auxilliary heterodimer- liferation and maturation via binding to nuclear retinoic ization partners for RARs, as well as for the vitamin D acid receptors (mainly RARa and RARc) which form receptor, liver X receptors, peroxisome proliferator- heterodimers with the 9-cis-RA receptor, RXRa.We activated receptors (PPARs) and other members of a have previously shown that mRNA expression of RARa superfamily of nuclear receptors (1). The retinoid- and RXRa is down-regulated in psoriatic lesions as activated RAR-RXR heterodimers recognize and bind compared with non-lesional human skin. In the present to RA-response elements (RAREs) in the promoter study, we investigated the protein expression of RARa, region of certain genes, thereby recruiting co-activators RARc and RXRa in normal and psoriatic skin using leading to transcriptional induction of the adjacent indirect immunofluorescence analysis. Epidermal kerati- gene (1). Retinoids may also interact with other nocytes of normal and non-lesional psoriatic skin signalling pathways, e.g. activator protein-1 (AP-1), displayed similar nuclear localization of all three which has been put forward as a key transcriptional receptors; RARa was detected with decreasing intensity regulator in the expression of many marker genes of from basal to suprabasal layers, RARc showed the keratinocyte differentiation.
    [Show full text]
  • The Impact of Vitamin D in Breast Cancer: Genomics, Pathways, Metabolism
    REVIEW ARTICLE published: 13 June 2014 doi: 10.3389/fphys.2014.00213 The impact of vitamin D in breast cancer: genomics, pathways, metabolism Carmen J. Narvaez 1, Donald Matthews 1,2, Erika LaPorta 1,2, Katrina M. Simmons 1,2, Sarah Beaudin 1,2 and JoEllen Welsh 1,3* 1 Cancer Research Center, University at Albany, Rensselaer, NY, USA 2 Department of Biomedical Sciences, University at Albany, Rensselaer, NY, USA 3 Department of Environmental Health Sciences, University at Albany, Rensselaer, NY, USA Edited by: Nuclear receptors exert profound effects on mammary gland physiology and have complex Carsten Carlberg, University of roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones Eastern Finland, Finland such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts Reviewed by: with its ligand 1α,25(OH) D to modulate the normal mammary epithelial cell genome Mieke Verstuyf, KU Leuven, Belgium 2 3 Moray J. Campbell, Roswell Park and subsequent phenotype. Observational studies suggest that vitamin D deficiency Cancer Institute, USA is common in breast cancer patients and that low vitamin D status enhances the *Correspondence: risk for disease development or progression. Genomic profiling has characterized many JoEllen Welsh, Cancer Research 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, Center, University at Albany, 1 providing insight into the molecular actions of 1α,25(OH) D and the VDR in regulation Discovery Drive, Rensselaer, 2 3 NY 12144, USA of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation e-mail: [email protected] of tumor metabolism and innate immune responses.
    [Show full text]
  • Atra) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous Atra Signaling
    1521-009X/45/7/846–854$25.00 https://doi.org/10.1124/dmd.117.075341 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 45:846–854, July 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Inhibition of the all-trans Retinoic Acid (atRA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous atRA Signaling Faith Stevison, Cathryn Hogarth, Sasmita Tripathy, Travis Kent, and Nina Isoherranen Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (F.S., S.T., N.I.); and School of Molecular Biosciences and the Center for Reproductive Biology, Washington State University, Pullman, Washington (C.H., T.K.) Received February 1, 2017; accepted April 18, 2017 ABSTRACT All-trans retinoic acid (atRA), the active metabolite of vitamin A, is a atRA concentrations in tissues. Following a single 2.5-mg/kg dose of Downloaded from ligand for several nuclear receptors and acts as a critical regulator of talarozole to mice, atRA concentrations increased up to 5.7-, 2.7-, and many physiologic processes. The cytochrome P450 family 26 (CYP26) 2.5-fold in serum, liver, and testis, respectively, resulting in induction enzymes are responsible for atRA clearance, and are potential drug of Cyp26a1 in the liver and testis and Rar b and Pgc 1b in liver. The targets to increase concentrations of endogenous atRA in a tissue- increase in atRA concentrations was well predicted from talarozole specific manner. Talarozole is a potent inhibitor of CYP26A1 and pharmacokinetics and in vitro data of CYP26 inhibition. After multiple CYP26B1, and has shown some success in clinical trials.
    [Show full text]
  • FROM ACNE to RETINOIDS and LYMPHOMAS Composed by Anders Vahlquist, Editor-In-Chief
    ISSN 0001-5555 Volume 92 2012 No. 3 Theme Section A Non-profit International Journal for Skin Research, Clinical Dermatology and Sexually Transmitted Diseases Official Journal of - The International Forum for the Study of Itch - European Society for Dermatology and Psychiatry THEME ISSUE: FROM ACNE TO RETINOIDS AND LYMPHOMAS COMPOSED BY ANDERS VAHLQUIST, Editor-IN-CHIEF Acta Dermato-Venereologica www.medicaljournals.se/adv Acta Derm Venereol 2012; 92: 227–289 THEME ISSUE: FROM ACNE TO RETINOIDS AND LYMPHOMAS Composed by Anders Vahlquist, Editor-in-Chief This theme issue of Acta Dermato-Venereologica bridges two bexarotene exert positive and negative effects far beyond seemingly unrelated diseases, acne and lymphoma, by inclu- those of pure RAR agonists. For the former drug, this is il- ding papers on retinoid therapy for both conditions. Beginning lustrated in a large trial on chronic hand eczema (p. 251) and with acne vulgaris, accumulating evidence suggests that diet in a pilot study of its use for congenital ichthyosis (p. 256). after all plays a role, which is ventilated in a commentary (p. For bexarotene, a new Finnish study shows 10 years expe- 228) of a prospective study using low- and high-calorie diets rience of this therapy in severe cutaneous lymphoma (p. 258). in adolescents with acne (p. 241). Acne treatment regimes Depending on the stage of the disease, lymphomas can also usually differ from one country to another; a Korean survey be treated for instance with photodynamic therapy (p. 264) (p. 236) combined with a review on how to treat post-acne and methotrexate (p. 276).
    [Show full text]
  • Synthesis of Biotinylated Retinoids for Cross-Linking and Isolation of Retinol Binding Proteins
    Tetrahedron 58 (2002) 6577–6584 Synthesis of biotinylated retinoids for cross-linking and isolation of retinol binding proteins Nasri Nesnas,a Robert R. Randob,* and Koji Nakanishia,* aDepartment of Chemistry, Columbia University, New York, NY 10027, USA bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA Received 11 June 2002; accepted 21 June 2002 This article is dedicated to Professor Yoshito Kishi on his receipt of the Tetrahedron Prize Abstract—The synthesis of (3R )-3-[Boc-Lys(biotinyl)-O ]-11-cis-retinol bromoacetate and 3-[Boc-Lys(biotinyl)-O ]-all trans-retinol chloroacetate is described. These biotinylated retinoids are instrumental in labeling the retinol binding proteins (RBPs) via a nucleophilic displacement of the haloacetate by a residue in the binding site of the protein. The covalently linked biotin will allow for a facile isolation and purification of the protein on a streptavidin column thus rendering the protein ready for a tryptic digest followed by mass spectrometric analysis. The 11-cis retinoid was synthesized via metal reduction of an alkyne intermediate generated from a Horner–Wadsworth–Emmons (HWE) reaction whereas the all-trans was synthesized via two consecutive HWE couplings. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction some are involved in catalyzing esterification, hydrolysis, and isomerization of retinols at various stages in the visual Retinoids are derivatives of vitamin A (all trans-retinol) cycle. A summary of the mammalian visual cycle is which can generally be synthesized for studies directed to a presented in Fig. 2. The visual protein, rhodopsin, is better understanding of human and non-human vision.
    [Show full text]